title: NEDD4 E3 ligase inhibits the activity of the Hippo pathway by targeting LATS1 for degradation.
abstract: Proper regulation of cell proliferation, cell apoptosis, and cell death are vital for the development and survival of living organisms. Failure or dysfunction of any of these processes can have devastating effects, including cancer. The Hippo pathway, first discovered in Drosophila, has been found to be a major growth-regulatory signaling pathway that controls these crucial processes and has been implicated in cell-progress regulation and organ size determination. Abnormal regulation of this pathway has been found in several cancer types. However, the mechanisms that regulate the pathway and its core members yet have to be elucidated. One of the main core components of this pathway is LATS1, a serine/threonine kinase. Therefore, understanding how LATS1 activity is regulated is expected to shed light on new mechanisms that regulate the Hippo pathway. In the current work, we identified several potential LATS1 regulators and proved that NEDD4 E3 ubiquitin ligase controls LATS1 stability. We demonstrate that NEDD4 directly interacts with LATS1, leading to ubiquitination and decreased levels of LATS1 and, thus, increased YAP localization in the nucleus, which subsequently increases the transcriptional activity of YAP. As such, we show that NEDD4 acts as an additional regulator of the Hippo pathway on the protein level via interactions between WW domain-containing and PPxY motif-containing proteins. These findings might be applied in the development of new therapeutic approaches through the activation of LATS1.
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research; IMRIC; Hebrew University-Hadassah Medical School; Jerusalem, Israel; Al Quds-Bard Honors College; Al-Quds University; East Jerusalem-Abu Dies, Palestine.
authors.forename: Zaidoun
authors.initials: Z
authors.lastname: Salah
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research; IMRIC; Hebrew University-Hadassah Medical School; Jerusalem, Israel.
authors.forename: Sherri
authors.initials: S
authors.lastname: Cohen
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research; IMRIC; Hebrew University-Hadassah Medical School; Jerusalem, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Itzhaki
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research; IMRIC; Hebrew University-Hadassah Medical School; Jerusalem, Israel.
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
mesh_terms: D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011392:Proline / Q000031:analogs & derivatives / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D009687:Nuclear Proteins; C487612:PPXY ligand; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D011392:Proline; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Hippo pathway; LATS1; NEDD4; WW domain; protein-protein interaction